Elsevier

Brain Stimulation

Volume 13, Issue 6, November–December 2020, Pages 1535-1547
Brain Stimulation

Disruption of hippocampal rhythms via optogenetic stimulation during the critical period for memory development impairs spatial cognition

https://doi.org/10.1016/j.brs.2020.08.011Get rights and content
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Highlights

  • Optogenetic stimulation of the medial septum in rat pups results in precise EEG regulation.

  • Optogenetic stimulation can severely disrupt normal oscillatory activity.

  • Disrupting endogenous EEG activity during the critical period impairs spatial cognition.

  • Cognitive dysfunction after optogenetic disruption of EEG activity is not due to cell loss.

Abstract

Background

Hippocampal oscillations play a critical role in the ontogeny of allocentric memory in rodents. During the critical period for memory development, hippocampal theta is the driving force behind the temporal coordination of neuronal ensembles underpinning spatial memory. While known that hippocampal oscillations are necessary for normal spatial cognition, whether disrupted hippocampal oscillatory activity during the critical period impairs long-term spatial memory is unknown. Here we investigated whether disruption of normal hippocampal rhythms during the critical period have enduring effects on allocentric memory in rodents.

Objective/hypothesis

We hypothesized that disruption of hippocampal oscillations via artificial regulation of the medial septum during the critical period for memory development results in long-standing deficits in spatial cognition.

Methods

After demonstrating that pan-neuronal medial septum (MS) optogenetic stimulation (465 nm activated) regulated hippocampal oscillations in weanling rats we used a random pattern of stimulation frequencies to disrupt hippocampal theta rhythms for either 1Hr or 5hr a day between postnatal (P) days 21–25. Non-stimulated and yellow light-stimulated (590 nm) rats served as controls. At P50-60 all rats were tested for spatial cognition in the active avoidance task. Rats were then sacrificed, and the MS and hippocampus assessed for cell loss. Power spectrum density of the MS and hippocampus, coherences and voltage correlations between MS and hippocampus were evaluated at baseline for a range of stimulation frequencies from 0.5 to 110 Hz and during disruptive hippocampal stimulation. Unpaired t-tests and ANOVA were used to compare oscillatory parameters, behavior and cell density in all animals.

Results

Non-selective optogenetic stimulation of the MS in P21 rats resulted in precise regulation of hippocampal oscillations with 1:1 entrainment between stimulation frequency (0.5–110 Hz) and hippocampal local field potentials. Across bandwidths MS stimulation increased power, coherence and voltage correlation at all frequencies whereas the disruptive stimulation increased power and reduced coherence and voltage correlations with most statistical measures highly significant (p < 0.001, following correction for false detection). Rats receiving disruptive hippocampal stimulation during the critical period for memory development for either 1Hr or 5hr had marked impairment in spatial learning as measured in active avoidance test compared to non-stimulated or yellow light-control rats (p < 0.001). No cell loss was measured between the blue-stimulated and non-stimulated or yellow light-stimulated controls in either the MS or hippocampus.

Conclusion

The results demonstrated that robust regulation of hippocampal oscillations can be achieved with non-selective optogenetic stimulation of the MS in rat pups. A disruptive hippocampal stimulation protocol, which markedly increases power and reduces coherence and voltage correlations between the MS and hippocampus during the critical period of memory development, results in long-standing spatial cognitive deficits. This spatial cognitive impairment is not a result of optogenetic stimulation-induced cell loss.

Graphical abstract

There is increasing evidence that there is a critical period for processing memories which depends on activity and plasticity mechanisms within the developing hippocampus. Whereas normal hippocampal EEG patterns are required for the normal development of spatial cognition, it is not known if disruption of EEG activity during this critical period of memory development has detrimental effects on cognition. Compared to rats with normal hippocampal oscillations during the third postnatal week, rats with optogenetically-disrupted hippocampal oscillations have substantial cognitive defects when the rats are tested as young adults in the active avoidance test. As demonstrated by the dwell-time maps demonstrating position of the rat during the testing, with hippocampal disruption rats do not avoid the shock zone (golden triangle) whereas control rats learn not to enter the shock zone. These results show that abnormal hippocampal oscillations during the critical period of memory have dire consequences on subsequent spatial cognition.

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Keywords

Memory
Development
Cognition
Optogenetic
Spectral power

Cited by (0)

1

Contributed equally to the manuscript.